Intrathecal Treatment in Cancer Patients Unresponsiveto Multiple Trials of Systemic Opioids

Sebastiano Mercadante, MD,*w Giuseppe Intravaia, RN,* Patrizia Villari, MD,*Patrizia Ferrera, MD,* Salvatore Riina, BS,* Fabrizio David, MD,*

and Salvatore Mangione, MDw

Abstract: The aim of this study was to evaluate the clinical

response to a combination of intrathecal morphine and

levobupivacaine in advanced cancer patients who were highly

opioid-tolerant, being previously treated with multiple opioid

trials unsuccessfully. Initial intrathecal morphine dose was

calculated from the previous opioid consumption using a

morphine oral-intrathecal ratio of 100:1. Then, doses of both

drugs were modied during the treatment according to the

clinical needs and balanced with adverse eects. Fifty-ve

patients were assessed during admission, before starting the

intrathecal treatment, during the titration phase, and followed

up to death, by frequent phone contacts or visits, as available.

Pain and symptom intensities were recorded before starting the

intrathecal treatment (T0), at time of hospital discharge (T dis),

and then at 1 month (T1), 3 months (T3), 6 months (T6)

intervals, and the last observation, at least 1 week before death

(T death). Fifty-ve patients were selected for starting an

intrathecal treatment. Thirty-two patients were males. The mean

age was 60 years (95% CI 57-63), and 65.4% of patients were

under 65 years. The most frequent indication was the presence

of adverse eects and poor pain control. Complete data with

adequate follow-up until death were available in 45 patients.

Statistical dierences in pain intensity were found at the

dierent time intervals examined until death. Statistical

decreases in the intensity of drowsiness and confusion were

found until 1 month after starting intrathecal therapy. Statistical

dierences were found in daily intrathecal morphine doses, with

a 3-fold increase at time of hospital discharge. Subsequently,

further increases in doses were not signicant. Conversely,

systemic opioids, expressed as oral morphine equivalents,

signicantly decreased at all the intervals examined until death.

Early complications included mild bleeding in 2 patients,

without consequences, headache in 4 patients, bladder cathe-

terization in 6 patients, reoperation for bleeding or changes of

catheter position in 4 patients, unrelated death in 1 patient, and

stroke in another 1. Late complications included local infection

in 2 patients, and discontinuation of intrathecal therapy due

to spinal compression. In patients who had received multiple

trial of opioids and routes of administration, the intrathecal

treatment started with an oral-intrathecal morphine conversion

ratio of 100:1, and local anesthetics at the most convenient

clinical doses provided a long-term improvement of analgesia,

with a decrease in adverse eects and opioid consumption until

death.

Key Words: cancer pain, intrathecal therapy, opioids

(Clin J Pain 2007;23:793798)

I t has been suggested that about 90% of cancer-relatedpain syndromes can be well controlled using theguidelines established by World Health Organization.1

Even when the basic principles for the use of analgesicdrugs are adhered to, some patients experience insucientpain relief or considerable adverse eects from systemicopioids, and 10% of the patients with unrelieved cancerpain may still represent a signicant number of patients.Opioid switching or even change of the route of opioidadministration may improve the opioid response in mostcases, and only a small proportion of patients with cancerpain should be candidates for spinal treatment.2 Spinalopioids are indicated if systemic treatment has failed,either because of inadequate analgesia or because ofintolerable side eects.3

The incidence of pain requiring spinal analgesiaremains unknown, as the size of the group from whichpatients are selected for spinal analgesia is rarelyreported, and spinal opioids are often started beforesystemic opioid administration is optimized. The indis-criminate use of spinal opioids cannot be recommendedand in some case the use is inappropriate.4 According tothe prevalent and more accepted opinion in the eld ofcancer pain, indications for the use of spinal opioidsshould include patients treated by systemic opioids witheective pain relief but with unacceptable side eects, orunsuccessful treatment with sequential strong opioid drugtrials despite escalating doses.5 However, in most studiesof spinal therapy in cancer pain management, theselection of patients is often based on general consi-derations such as failure of traditional cancer painCopyright r 2007 by Lippincott Williams & Wilkins

Received for publication June 13, 2007; revised July 18, 2007; acceptedJuly 22, 2007.

From the *Anesthesia and Intensive Care Unit and Pain Relief andPalliative Care Unit, La Maddalena Cancer Center, Palermo;and wIntensive Care and Emergency, Palliative Medicine section,University of Palermo, Italy.

Reprints: Sebastiano Mercadante, MD, Anesthesia and Intensive CareUnit and Pain Relief and Palliative Care Unit, La Maddalena CancerCenter, Via S. Lorenzo 312, 90145 Palermo, Italy (e-mail:terapiadeldolore@lamaddalenanet.it).

ORIGINAL ARTICLE

Clin J Pain Volume 23, Number 9, November/December 2007 793

management approaches, so that some patients maypossibly receive spinal treatments regardless of a previousaggressive systemic approach including opioid and routeswitching. Thus, it is not clear at what point in the courseof the treatment spinal opioids should be initiated andwhich patients are ideal candidates.

Another controversial point regards the dose con-version to start intrathecal morphine. Titration could beunfeasible in these situations, where patients are alreadyreceiving high doses of systemic opioids and are sueringso much that they require a rapid pain control and/ordecrease of opioid-induced adverse eects intensity. Somekey factors having an impact upon the selection of astarting dose in the opioid-tolerant cancer populationhave been explored.6 Dierent oral-intrathecal ratioshave been proposed, ranging from 60 to 300:1.68 A veryhigh oral-intrathecal conversion ratio could be incon-venient for a selected population with high levels ofsystemic opioid tolerance, resulting in further sueringfor patients receiving high opioid doses. According tolocal policy, patients are candidates to spinal treatmentonly after multiple trials of opioids and routes ofadministration have failed. This means that this groupof patients is highly resistant to systemic opioids andrequire a more aggressive initial conversion ratio.

The aim of this study was to evaluate the clinicalresponse to a combination of opioids and local anes-thetics spinally administered in a cohort of advancedcancer patients who were strictly selected for thisindication. The second outcome was to evaluate thefeasibility of starting with a morphine oral-intrathecalmorphine of 100:1, and the subsequent dose changesduring the treatment until death.

PATIENTS AND METHODSA cohort of consecutive patients requiring intrathe-

cal therapy for cancer pain was prospectively surveyed fora period of 4 years (2003 to 2006). Inclusion criteria wereprevious trials with at least 3 opioids (multiple switchingfailure) and 2 routes of administration (including theintravenous one). Opioids available were oral andintravenous morphine, transdermal fentanyl, and metha-done. Institutional approval was obtained and informedconsent was obtained from all the patients who hadnormal cognition (otherwise consent was obtained byrelatives). All the procedures were carried out in theoperating theater with all aseptic precautions. Thepatients were sedated to comfort with propofol, andplaced in the lateral decubitus position. Using a standardtechnique, an intrathecal catheter was inserted at the mostappropriate metamer, corresponding to the most painfuldermatome (lumbar or thoracic). Catheter was tunneledsubcutaneously to the anterior abdominal wall andconnected to a port in a subcutaneous prepared pocket.A port needle, connected to a pump, was inserted. Acombination of local anesthetics and morphine wasstarted. The mixtures of morphine and levobupivacainewere as follows: at the beginning of treatment the dose

were levobupivacaine 12.5mg/d plus morphine at thestarting dosage calculated from the systemic daily dose(see below), diluted in saline, to provide an infusion rateof 2mL/h. The dose of levobupivacaine was increased to25mg/d before increasing the daily intrathecal morphine.

Initial intrathecal morphine dose was calculatedfrom the previous opioid consumption using an oral-intrathecal ratio of 100:1. According to a departmentpolicy, the conversion ratios used among opioids androutes of administration were the following, on the basisof known drug availability for oral, transdermal, andintravenous route of administration, and expressed asmg/d oral morphine 100= intravenous morphine 33=transdermal fentanyl 1= intravenous fentanyl 1=oralmethadone 20= intravenous methadone 16.9

Then, doses of both drugs were modied during thetreatment according to the clinical needs and balancedwith adverse eects. Intrathecal adjuvants, includingclonidine or ketamine, were added if necessary. Intrathe-cal Vancocin 50mg was also administered. Previoussystemic opioid doses were progressively tapered, afterhalving the doses in the rst 24 hours, when possible. Thecombination of the treatment was gradually changed tobring pain intensity to an acceptable level (numerical scaleabout 4/10). After achieving an adequate analgesia,patients were discharged home and frequent phonecontacts or visits, when possible, were maintained,eventually for changing pump content.

Syringe-pumps were used in hospital during dosetitration of the intrathecal treatment. Once stableintrathecal doses were achieved, balloon-type deviceswere provided for home infusions, and changes at 5 daysintervals.

AssessmentThe following parameters were recorded: age, sex,

primary cancer and known metastases, pain causes andmechanisms, and performance status. Patients wereassessed during admission, before starting the intrathecaltreatment, during the titration phase, and followed up todeath, by frequent phone contacts or visits, as available.Pain and symptom intensities were recorded beforestarting the intrathecal treatment (T0), at time of hospitaldischarge (T dis), and then at 1 month (T1), 3 months(T3), 6 months (T6) intervals, and the last observation, atleast 1 week before death (T death). Pain intensity wasrecorded by using a numerical scale from 0 to 10. Opioid-related symptoms, including nausea and vomiting,drowsiness, confusion, constipation, dry-mouth, and soon, using a scale from 0 to 3 (not at all, slight, a lot, andawful), were recorded at the same intervals. Symptomswere assessed by the patient. Type of opioid and dailysystemic opioid consumption, expressed in oral morphineequivalents, were recorded, as well symptomatic drugs.Immediate and late complications or adverse eectsattributable to intrathecal treatment were recorded.Caregivers were instructed to recognize any importantproblems. Emerging complications were also recorded.

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794 r 2007 Lippincott Williams & Wilkins

StatisticsFrequency analysis was performed using the Pear-

son w2 test. The Paired Samples student t test procedurewas used to compare the means of symptoms for a group.The Wilcoxon signed-rank test was used to compare thedierent nonparametric variables.

Analysis of the variance for repeated measures wasused to estimate the scores or the means of symptoms atthe dierent time intervals in the same group. All P valueswere 2-sided, and P values

anesthetics doses. In some patients with preexistentneurologic derangement, even low dose of local anes-thetics triggered or worsened numbness. One patient wasreoperated due to bleeding of subcutaneous pocket. In 3patients intrathecal catheter entrance was changed toimprove metameric analgesia. One patient died unexpect-edly 3 days after starting the intrathecal treatment. Strokewas diagnosed in another patient who died duringadmission. In both cases, however, no relationship withthe spinal treatment was found.

Late ComplicationsIn 1 patient, catheter was removed and then

replaced due to the appearance of signs of local infection.One patient stopped the intrathecal treatment due toprogressive paralysis associated with the development ofspinal cord compression. He developed severe drowsinessand bradypnea, probably due to relative intrathecalopioid overdosing. Intrathecal morphine was discontin-ued, and patient recovered in a few days. Small doses oftransdermal fentanyl were sucient to control his pain.

In 1 patient, the presence of local infection wasobserved, but she was not reoperated as she wasconsidered close to death.

DISCUSSIONSeveral studies have reported the advantages of the

intrathecal route on the epidural route, which include abetter pain control, a lesser rate of late complications,lower volumes and opioid doses,1018 and the possible use

of internalized pumps.8 A synergistic eect of intrathecalmorphine and local anesthetics has been shown, particu-larly in patients receiving previous high systemic opioiddoses.10,17 Thus, the combination of intrathecal morphineand local anesthetics for the management of dicult painconditions has become a standard practice at ourinstitution since its opening.

Many studies have shown favorable outcomes withspinal treatment. However, details on the previoussystemic treatment and optimization of opioid therapy,and other data are lacking. Thus, it is dicult to judge thereal need and ecacy of a spinal treatment in patientsreally unresponsive to systemic opioids and whether theoutcomes obtained are based on an unselected populationnot adequately treated. In a comparative study, animplantable drug delivery system for intrathecal mor-phine provided a better impact on pain, opioid-relatedadverse eects, and survival, compared with comprehen-sive medical management.8 Several criticisms, principallyregarding patients selection and denition of standardcare, have been reported. Moreover, local anesthetics,probably given at low doses due the limitation of theinternal pump volumes, were added in some cases, andalso a small number of patients taking nonopioids onlywere included. The present study demonstrated thatintrathecal treatment is really eective even in a veryselected population, that is patients who had receivedaggressive systemic treatments, including at least 3 trialswith dierent opioids, and 2 routes of administration,including intravenous morphine, and not only in patients

TABLE 2. Pain and Symptom Intensity Recorded at Intervals Described in the Text

T0 T dis T1 T3 T6 T Death

No. patients 55 53 25 12 3 45Pain 7.98 3.00 3.87 3.92 3 3.92

7.4-8.5 2.3-3.6 3.1-4.6 2.4-5.4 0.5-5.5 2.4-5.4P

generically considered unresponsive or receiving a certaindose of systemic opioids.8 Doses used in this study alsoconrm the complexity of the pain syndromes, reaching amean of about 20 and 54mg/d of intrathecal morphineand levobupivacaine, respectively, in a mean survival timeof 71 days, with a relatively minimal opioid escalationindex of 0.19mg/d. In a previous experience at homeusing lower starting intrathecal opioid doses, the escala-tion index was 0.4mg/d,19 which indicates that the initialstarting doses do not inuence the subsequent intrathecalmorphine dose escalation. The average dose escalatedquickly during titration and then stabilized, as describedin other studies of cancer patients in comparison with amore gradual, linear increase in dose observed innoncancer patients.20 As expected, intrathecal doses ofmorphine were relatively high, but similar with thosereported in a similar group of highly opioid-tolerantpatients with pancreatic cancer.21 Of interest, 9 patientsrequired more than 30mg/d, and 4 of them 50mg/d ofintrathecal morphine. Very high doses of intrathecalmorphine (140mg/d) have been occasionally reported.22

Doses of levobupivacaine remained relatively stable andincreased, but not statistically, close to death, possiblydue to the development of tachyphylaxis.

Neuroexcitatory eects observed with high doses ofopioids are of concern.23 In this study this was notapparently observed, possibly due to the concomitant useof local anesthetics, which may have some protectiveeects,24 although this remains just a mere speculation.Intrathecal doses up to 73mg/d were not associated withsedation or adverse eects which prevented achievementof pain control.7 The incidence of adverse eects ofintrathecal morphine does not seem to be associated withits doses.25 It seems that impaired rostral diusion isdeterminant for inducing spinal cord excitation resultingin myoclonus,26 rather than the dose itself.

Another controversial point is the starting dose ofintrathecal morphine. Long-term dose titration could bedetrimental for patients, increasing their suering andreducing their compliance. Doses should be adjusted byage, injection site, and patients medical condition, anddegree of tolerance to opioids.27 Some key factors havingan impact upon the selection of a starting dose in theopioid-tolerant cancer population have been described.6

An oral-intrathecal ratio of 200 to 300:1 has beensuggested, and some predictive factors, including previousopioid dose have been recommended.5,8 It is well knownthat some cross tolerance exists between spinal andsystemic routes, although some levels of asymmetrictolerance may occur,28 and could be used to take someadvantages in terms of opioid dosing. Patients who havebeen intensively treated with several opioids, adminis-tered by dierent routes, are challenging, and dosetitration starting with minimal doses of intrathecalmorphine may be time loosing in a population who is,per denition, really suering. A more aggressive ratio,100:1, used in this trial was eective and did not result inrelevant opioid-related complications. The choice of suchstarting doses of intrathecal morphine were based on

local policy and previous experience in patients highlytolerant to systemic opioids. Other researchers have beenusing even important conversion ratios of 60:1.717 Infact, the parameters to candidate patients to theintrathecal treatment were dierent attempts with opioidsand routes, including the use of intravenous route,retained to be able to improve the opioid response insome dicult situations.29 Of interest, it should beoutlined that even so, a further dose titration wasrequired, and doses at discharge, that is in a phase ofstabilization when analgesia and adverse eects wereconsidered acceptable, were 3 times as higher as thestarting doses (about an oral-nal intrathecal morphineratio of 33:1). This observation suggests that the risk ofovermedication is unlikely in such kind of patients, alsoconsidering that local anesthetics at optimized doses wereadded to improve analgesia. Using opioids alone prob-ably would have required even higher starting doses or aprolonged doses titration. Therefore, patients selectedafter stringent criteria may reduce time of dose titrationto achieve adequate analgesia by using a more incisiveoral-intrathecal morphine conversion ratio. Most patientscould stop systemic opioids or decreasing their doses untildeath. This resulted in a clear improvement of adverseeects, particularly drowsiness, after starting the intra-thecal treatment. Deterioration of the clinical conditioncould be responsible of some adverse eects, commonlyattributed to opioids, particularly in last weeks of life,when it is dicult to distinguish between opioid-relatedeects and disease progression-related symptoms.

In an algorithm resulting from a consensus con-ference, intrathecal dugs were arranged in a hierarchyaccording to evidence of safety, ecacy, and experience.A combination of morphine and local anesthetics wasplaced as second step.30 Although these guidelines areprobably appropriate for noncancer pain, clinical sensesuggests that cancer patients highly tolerant to systemicopioids require an intensive polyanalgesic intervention toimprove analgesia.1317

Early and late complication rates, either technical orpharmacologic, were similar to those reported in previousstudies,2,12 and managed accordingly. Urinary retentionoccurred in 6 patients and was specically attributedto the intrathecal treatment. Similarly, numbness wasdicult to assess, particularly with phone contacts. Forboth problems a preexisting neurologic damage cannot beexcluded. Moreover, the entity of these problems wasdicult to distinguish due to the general derangement ofthe clinical conditions in the long-term period. Spinalcompression may produce neurologic impairment duringlong-term intrathecal treatment.31 In 1 patient whodeveloped spinal cord compression, the intrathecaltherapy was discontinued, and transdermal fentanylwas found to be eective in relieving pain. It can behypothesized that the cord compression relieves pain byinterrupting the nociceptive pathway, and consequentlythe current intrathecal morphine dose was relativelyoverdosed as the neurologic damage was completed andthe pain had been relieved.32 Evidence exists that the

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formation of granulomatous masses are related to the useof higher doses at high concentration.33,34 Although nosuspicion for the development of intrathecal granulomasraised by patients assessment and clinical course,this doubt could not be resolved, as autoptic data werenot available.

This study rst, provided further information on theoutcome of an intrathecal treatment in highly opioidtolerant patients. Given the complexity of this kind ofpatients and the need to provide individually the bestoutcome, controlled studies are really dicult to performand often provide information, which may be inferred byprotocol limitation, not always ethically acceptable.

In conclusion, in patients who had received multipletrial of opioids and routes of administration, theintrathecal treatment started with an oral-intrathecalmorphine conversion ratio of 100:1, and local anestheticsat the most convenient clinical doses, provided a rapidand long-term improvement of analgesia, with a decreasein adverse eects and opioid consumption until death.

REFERENCES1. Hanks GW, De Conno F, Cherny N, et al. Expert working group of

the research network of the European association for palliative care.Morphine and alternative opioids in cancer pain: the EAPCrecommendations. Br J Cancer. 2001;84:587593.

2. Burton A, Rajagopal A, Shah H, et al. Epidural and intrathecalanalgesia is eective in treating refractory cancer pain. Pain Med.2004;5:239247.

3. Mercadante S. Problems of long-term spinal opioid treatment inadvanced cancer patients. Pain. 1999;79:113.

4. Mercadante S, Agnello A, Armata MG, et al. The inappropriate useof the epidural route in cancer pain. J Pain Symptom Manage.1997;13:352355.

5. Krames ES. Intrathecal infusional therapies for intractable pain:patient management guidelines. J Pain Symptom Manage. 1993;8:3646.

6. Du Pen SL, Williams AR. The dilemma of conversion from systemicto epidural morphine: a proposed conversion tool for treatment ofcancer pain. Pain. 1994;56:113118.

7. Van Dongen RTM, Crul BJP, van Egmond J. Intrathecaladministration of bupivacaine diminishes morphine dose progres-sion during long-term intrathecal infusion in cancer patients. ClinJ Pain. 1999;15:166172.

8. Smith TJ, Coyne PJ, Staats PS, et al. An implantable drug deliverysystem (IDDS) for refractory cancer pain provides sustained paincontrol, less drug-related toxicity, and possibly better survivalcompared with comprehensive medical management (CMM). J ClinOncol. 2005;16:825833.

9. Mercadante S, Ferrera P, Villari P, et al. Rapid switching betweentransdermal fentanyl and methadone. J Clin Oncol. 2005;23:52295234.

10. Nitescu P, Appelgren L, Linder LE, et al. Epidural versusintrathecal morphine-bupivacaine: assessment of consecutive treat-ments in advanced cancer pain. J Pain Symptom Manage. 1990;5:1826.

11. Nitescu P, Hultman E, Appelgren L, et al. Bacteriology, drugstability and exchange of percutaneous delivery systems andantibacterial lters in long-term intrathecal infusion of opioid drugsand bupivacaine in refractory pain. Clin J Pain. 1992;8:324337.

12. Nitescu P, Sjoberg M, Appelgren L, et al. Complications ofintrathecal opioids and bupivacaine in the treatment of refractorycancer pain. Clin J Pain. 1995;11:4562.

13. Crul BJ, Delhaas EM. Technical complications during long-termsubarachnoid or epidural administration of morphine in terminallyill cancer patients: a review of 140 cases. Reg Anesth. 1991;16:209213.

14. Sjoberg M, Appelgren L, Einarsson S, et al. Long-term intrathecalmorphine and bupivacaine in refractory cancer pain. I. Results fromthe rst series of 52 patients. Acta Anesthesiol Scand. 1991;35:3043.

15. Sjoberg H, Karlsson P, Nordborg C, et al. Neuropathologic ndingsafter long-term intrathecal infusions of morphine and bupivacainefor pain treatment in cancer patients. Anesthesiology. 1992;76:173186.

16. Sjoberg M, Nitescu P, Appelgren L, et al. Long-term intrathecalmorphine and bupivacaine in patients with refractory cancer pain.Anesthesiology. 1994;80:284297.

17. van Dongen RTM, Crul BJP, De Bock M. Long-term intrathecalinfusion of morphine and morphine/bupivacaine mixtures in thetreatment of cancer pain: a retrospective analysis of 51 cases. Pain.1993;55:119123.

18. Baker L, Lee M, Regnard C, et al. Evolving spinal analgesia practicein palliative care. Palliat Med. 2004;18:507515.

19. Mercadante S. Intrathecal morphine and bupivacaine in advancedcancer pain patients implanted at home. J Pain Symptom Manage.1994;9:201207.

20. Paice JA, Penn R, Shott S. Intraspinal morphine for chronic pain:a retrospective, multicenter study. J Pain Symptom Manage. 1996;11:7180.

21. Gilmer-Hill H, Boggan J, Smith KA, et al. Intrathecal morphinedelivered via subcutaneous pump for intractable pain in pancreaticcancer. Surg Neurol. 1995;51:611.

22. Tamakawa S, Iwanami Y, Ogawa H. High-dose intrathecalmorphine to control cancer paina case report. J Pain SymptomManage. 1998;15:7072.

23. Parkinson SK, Bailey SL, Little WL, et al. Myoclonic seizureactivity with chronic high-dose spinal opioid administration.Anesthesiology. 1990;72:743745.

24. Koppert W, Ostermeir N, Sittl R, et al. Low-dose-lidocaine reducessecondary hyperalgesia by a central mode of action. Pain. 2000;85:217224.

25. Raaeli W, Marconi G, Fanelli G, et al. Opioid-related side eectsafter intrathecal morphine: a prospective, randomized, double-blinddose-response study. Eur J Anesthesiol. 1006;23:605610.

26. Kloke M, Bingel U, Seeber S. Complications of spinal opioidtherapy: myoclonus, spastic muscle tone and spinal jerking. SupportCare Cancer. 1994;2:249252.

27. APS. Guidelines for the Management of Cancer Pain in Adults andChildren. Glenview, IL: American Pain Society; 2005.

28. Pfeifer B, Sernaker H, Ter Horst U, et al. Cross-tolerance betweensystemic and epidural morphine in cancer patients. Pain. 1989;39:181187.

29. Enting RH, Oldenmerger WH, van der Rijt CC, et al. A prospectivestudy evaluating the response of patients with unrelieved cancer painto parenteral opioids. Cancer. 2002;94:30493056.

30. Peng P, Massicotte EM. Polyanalgesic consensus conference 2003;an update on the management of pain by intraspinal drug deliveryreport of an expert panel. J Pain Symptom Manage. 2004;27:540563.

31. Van Dongen RTM, van Ee R, Crul BJP. Neurological impairmentduring long-term intrathecal infusion of bupivacaine in cancerpatients: a sign of spinal cord compression. Pain. 1997;69:205209.

32. Quevedo F, Walsh D. Morphine-induced ventilatory failure afterspinal cord compression. J Pain Symptom Manage. 1999;18:140142.

33. Hassenbusch SJ, Portenoy RK, Cousins M, et al. Spinal cordcompression from intrathecal catheter-tip inammatory mass: casereport and a review of etiology. Reg Anesth Pain Med. 2004;29:237242.

34. Miele VJ, Price KO, Bloomeld S, et al. A review of intrathecalmorphine therapy related granulomas. Eur J Pain. 2006;10:251261.

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